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Amiodarone (AMD) is a potent antiarrhythmic drug with high efficacy for treating atrial fibrillation and tachycardia. The pharmacologic profile of AMD is complex. AMD possesses biophysical characteristics of all of class I, II, III, and IV agents. Despite its adverse side effects, AMD remains the most commonly prescribed antiarrhythmic drug. AMD was described to prolong the QT interval and can lead to torsades de pointes. Our goal was to study the effects of AMD on peak and late sodium currents (I Na,P  and I Na,L ) and determine whether these effects change as AMD is metabolized into  N -desethylamiodarone (DES). We hypothesized that AMD and DES block both I Na,P  and I Na,L  with similar profiles due to structural similarities. Given the inherent small amounts of I Na,L  in Na V 1.5, we screened AMD and DES against the Long QT-3-causing mutation, ΔKPQ, to better detect any drug-mediated effect on I Na,L . Our results show that AMD and DES do not affect WT or ΔKPQ activation; however, both drugs altered the apparent valence of steady-state fast-inactivation. In addition, AMD and DES preferentially block ΔKPQ peak conductance compared to WT. Both compounds significantly increase I Na,L  and window currents. We conclude that both compounds have pro-arrhythmic effects on Na V 1.5, especially ΔKPQ; however, DES seems to have a greater pro-arrhythmic effect than AMD.

Effects of Amiodarone and N-desethylamiodarone on Cardiac Voltage-Gated Sodium Channels